Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:49]=[CH:48][C:25]([O:26][CH2:27][CH:28]([O:44][C:45](=[O:47])[CH3:46])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:49]=[CH:48][C:25]([O:26][CH2:27][CH:28]([O:44][C:45](=[O:47])[CH3:46])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)OC(COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)COc1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC(COc1ccc(CCCO)cc1)COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 70 °C
Yield: 99.2 %

Procedure:
A solution of (2R and 2S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-acetoxypropane (7.38 g, 10.8 mmol) in tetrahydrofuran (100 ml) was treated with acetic acid (3.7 ml) and 24 ml (24 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and the resulting mixture was heated at 70° C. for 4 hours. The cooled mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 75:25) gave 4.76 g (97%) of the title alcohol as an oil.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])=[O:7]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:1]#[N:2])[CH2:11][CH2:10][C:9]1=[O:14])=[O:7]
Reactant: COC(=O)C12CC1CCC2=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1C(=O)CCC1CC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
In argon atmosphere, potassium cyanide (260 mg, 4 mmol) and 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester (462 mg, 3 mmol) were added to hexamethylphosphoric triamide (3 ml). The mixture was stirred at the room temperature for 24 hours and was treated in accordance with the process of Preparation 4 to obtain 300 mg of 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester. Yield: 55%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:33]([CH3:40])[CH3:32])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
To a stirred DCM (15 mL) solution of the product from Example 1 (58 mg), 4-(dimethylamino)butyric acid hydrochloride (28.2 mg) and TEA (0.059 mL) was added HATU (58.7 mg) under nitrogen. The resulting solution was stirred at rt for 16 h. The solvent was evaporated and the residue was taken up in MeOH and the crude product purified by RPHPLC to afford the title compound 5 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:7]=[CH:6]2.C(Cl)(Cl)Cl.Cl.C(COC)OC>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 50 °C
Reaction time: 23 h
Yield: 57.5 %

Procedure:
A mixture of 90 mg (0.37 mmol) of methyl (+)-α-(6-methoxy-2-naphthyl)propionate having a 100% optical purity [α]D20 +78.2° (CHCl3)], 1 ml of 12N aqueous hydrochloric acid and 1 ml of dimethoxyethane was stirred at 50° C. for 23 hours. After adding 10 ml of water, the mixture was extracted with diethyl ether (8 ml×3), and the extract was washed with water (3 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography [silica gel, hexane+ethyl acetate (1:2)] to obtain 49 mg of (+)-α-(6-methoxy-2-naphthyl)propionic acid as colorless crystals. Yield, 63%.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3][CH:2]=1.[CH:14](OCC)=[O:15].[H-].[Na+]>C(COC)OC.C(OCC)(=O)C>[CH:14]([CH:8]([CH2:7][C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:15]
Reactant: CCOC(=O)CCc1cncnc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C=O)Cc1cncnc1
Reaction time: 24 h

Procedure:
A mixture of ethyl 3-(5-pyrimidyl)propionate (2.28 g) and ethyl formate (1.41 ml) dissolved in dry dimethoxyethane (5 ml) was added dropwise over 30 min to a suspension of sodium hydride (60%, 4.0 g) in DME (5 ml) under nitrogen, keeping the temperature below 0° C. Stirring was continued for a further 24 h, then the mixture was poured onto ice and washed with ether. The aqueous layer was adjusted to pH 7, then evaporated and the residue extracted with acetone. Filtration and evaporation gave crude product, which was taken up in ethyl acetate, charcoaled, dried and evaporated to give ethyl 2-formyl-3-(5-pyrimidyl)propionate. Like other compounds of this type, this proved difficult to characterise and was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)[N:22](O)C(=O)C1.C1(N=C=NC2CCCCC2)CCCCC1.N>C(OCC)(=O)C.O1CCCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:17])[NH2:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(N)=O)CC1
Reaction time: 8 h

Procedure:
A solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (15 g, 61.7 mmol) and 1-hydroxysuccinimide (76 g, 61.7 mmol) in ethyl acetate (200 ml) was treated with a solution of dicyclohexylcarbodiimide (12.7 g, 61.7 mmol) in ethyl acetate (50 ml). After stirring overnight the mixture was filtered and evaporated affording a yellow solid. This was redissolved in tetrahydrofuran (300 ml) and treated gaseous ammonia was bubbled through the solution for 15 minutes. Filtration afforded a white solid which was stirred in water (200 ml) for 1 hour. Filtration and drying afforded a white solid (11.3 g, 76%).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[NH2:19][C:20]1([C:29]#[N:30])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[C:29]([C:20]1([NH:19][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)#[N:30]
Reactant: N#CC1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC2(C#N)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 0.08 h

Procedure:
A 30 mL vial is charged with 2-cyclobutoxy-3-methyl-benzoic acid (734 mg, 3.56 mmol) and dry DCM (10 mL). A stirring bar is added and stirring is initiated. After 5 min, HTBU (1.35 g, 3.56 mmol) is added. After 5 min, 2-amino-indane-2-carbonitrile. (308, 563 mg, 3.56 mmol) is added followed by DIPEA (1.5 mL, 8.95 mmol). The reaction is allowed to stir for 38 h. Analysis of the reaction mixture by tlc (silica, 15% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (60 mL). This is washed saturated aqueous NaHCO3 (2×20 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.2 g of thick black oil. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 4 column volumes followed by a linear gradient to 50% EtOAc over 8 column volumes and then 90% EtOAc in heptanes for 2 column volumes. 17 mL fractions of UV active eluent are collected. Fractions 27 through 30 are combined and evaporated in vacuo to give white solid (0.51 g, 41%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([Cl:33])=[CH:26][N:25]=1.C(N(CC)CC)C>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:31]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc(Cl)cnc4Cl)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), 2,5-dichloropyridine-3-carbonyl chloride (0.42 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in THF (30 mL) was stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.50 g of the product (54% yield): mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.53-2.58 (m, 2H), 2.83-2.97 (m, 1H), 4.93 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.3 Hz, 1H), 7.82-7.91 (m, 3H), 8.28 (d, J=2.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 9.35 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 130.3, 131.6, 133.4, 134.9, 137.8, 138.0, 145.0, 148.8, 164.1, 166.9, 167.5, 169.8, 172.8; Anal. calcd for C20H14Cl2N4O5.0.2H2O: C, 51.68; H, 3.12; N, 12.05. Found: C, 51.64; H, 3.05; N, 11.98.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:11]=[C:10]([C:9]2[O:19][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: COc1cc(C(=O)Nc2ccccc2O)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1C

Procedure:
3-Methoxy-4-methyl benzoic acid (1.2 g, 7.2 mmol) and thionyl chloride (10 mL) was heated to reflux conditions under argon until no starting material was observed by TLC. After cooling mixture to rt and concentration in vacuo, the resulting brown oil was dissolved in THF (15 mL) and slowly added to a cooled mixture of 2-aminophenol (780 mg, 7.1 mmol), diisopropylethyl amine (1.5 mL, 8.6 mmol) and THF (20 mL) at 0° C. Reaction mixture was allowed to warm to rt. After one hour, no starting material acid was observed by TLC. After concentrating reaction mixture in vacuo, the resulting brown oil was purified by flash chromatography on silica gel, using 1:4 EtOAc:hexanes. This afforded the desired intermediate, N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide, as a yellow solid. A mixture of N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide (1.5 g, 5.88 mmol), toluene (30 mL), p-toluenesulfonic acid monohydrate (7.6 g, 40 mmol) and molecular sieves was refluxed overnight. After cooling reaction to rt, filtered washing with warn chloroform and concentrated filtrate in vacuo. The resulting brown oil was purified by flash chromatography on silica gel using 1:4 EtOAc:hexanes to give the desired intermediate, 2-(3-methoxy-4-methylphenyl)-1,3-benzoxazole, as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[C:6](CC)[C:5]=1[O:15][CH:16]([CH3:18])[CH3:17])([O-:3])=[O:2].[OH-].[K+].Cl>C(O)C.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:15][CH:16]([CH3:18])[CH3:17])([O-:3])=[O:2]
Reactant: CCc1c(C(=O)[O-])ccc([N+](=O)[O-])c1OC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
To a solution of 4-nitro-3-isopropoxy-ethylbenzoate (11.85 g, 0.047 mol) in ethanol (200 mL) was added a solution of potassium hydroxide (2.6 g, 0.047 mol) in water (5 mL). The reaction mixture was heated to reflux for 2 hours. The ethanol volume was reduced to 100 mL and the mixture then poured into 1 N HCl (100 mL). The crystals that precipitated, were filtered off and dried in a vacuum oven to yield 9.35 g (88%) of 4-nitro-3-isopropoxybenzoic acid. MS ES− 225, ES+ 223.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].Br[C@@H]1C[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]1O.C(#[N:18])C.S(=O)(=O)(O)O>O>[NH2:18][C@@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][C@@H:1]1[OH:4]
Reactant: CC(=O)O
Reactant: CC#N
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 60 °C
Reaction time: 0.58 h

Procedure:
Into a 200 ml four-neck flask, 50 ml of acetic acid, 21.3 g (0.1 mol) of trans-(±)-2-bromoindan-1-ol (I), and 4.52 g (0.11 mol) of acetonitrile were introduced. While the mixture was stirred, 12.1 g (0.12 mol) of 97% sulfuric acid was dropwise added thereto at 23°-25° C. in a period of 35 minutes. The crystal totally disappeared. The reaction liquid was further stirred at room temperature for 20 hours. When dispersed into 200 ml of water, the reaction liquid became a white slurry. As this slurry was heated at 60° C. for 6 hours while being stirred, the crystal was totally dissolved. The reaction liquid was cooled to room temperature, washed twice with 100 ml of methylene chloride, and then subjected to liquid separation. When an aqueous solution of 25% sodium hydroxide was added to the water phase to attain a pH of 11, a white crystal was deposited. This crystal was filtered off under reduced pressure, washed with 100 ml of water, and then dried in vacuo to yield 5.33 g of cis-(±)-1-aminoindan-2-ol (I) as a white crystal. Its purity determined by a liquid chromatography was 96.9%.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:35]
Reactant: Cc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 153 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-methylphenyl)ethanone, the mixture was stirred for 5 hours at room temperature. Aqueous 1N sodium hydroxide was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was Washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (66 mg, 51% yield).
Reaction SMILES: [CH3:1][N:2]1[C:31](=[O:32])[CH:5]2[CH:6](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=4)=[CH:17][N:16]=3)[N:7]3[CH:12]([CH:4]2[C:3]1=[O:33])[CH2:11][CH2:10][CH2:9][CH2:8]3.BrC1C=CC(/C=C/C2N3C(CCCC3)C3C(=O)N(C)[C:54](=[O:55])C23)=NC=1.COC1C=CC=CC=1B(O)O>>[CH3:54][O:55][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[CH:6]2[N:7]3[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:4]3[C:3](=[O:33])[N:2]([CH3:1])[C:31](=[O:32])[CH:5]23)=[N:16][CH:17]=1
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)cn1
Agent: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(/C=C/C2C3C(=O)N(C)C(=O)C3C3CCCCN23)nc1

Procedure:
The title compound is prepared analogously to the compound from Example 17 from 42 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-2-methyloctahydropyrrolo[3,4-a]-indolizine-1,3-dione (from Example 6, racemic mixture 3) and 18 mg of 2-methoxyphenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]O>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14])[C:4]=2[CH:3]=1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Reactant: CN(C)CCCO
Solvent: C1COCCO1
Product: CN(C)CCCOc1cc(=O)oc2ccc(Cl)cc12
Product: Cl
Yield: 73 %

Procedure:
Is prepared via method B from 6-chloro-4-hydroxycoumarin and 3-dimethylamino-propan-1-ol using 4M HCl in dioxane to form the title compound as the hydrochloric acid salt (332 mg, 73%). 1H NMR (DMSO-d6, 300 MHz) δ 10.23 (1H, s), 7.88 (1H, d, J=2.75 Hz), 7.73 (1H, dd, J=2.75, 9 Hz), 7.48 (1H, d, J=9Hz), 6.0 (1H, s), 4.31 (2H, t, J=5.75 Hz), 3.28 (2H, m), 2.80 (3H, s), 2.80 (3H, s), 2.24 (2H, m); MS (ESI, Pos.) calcd for C14H16ClNO3 m/z [M+H]=282.1, found 282.1.
Reaction SMILES: [C:1]([CH2:5][C:6](OCC)=[O:7])(=O)[CH2:2][CH3:3].CS(O)(=O)=O.[CH2:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[NH:23])[CH2:17][CH3:18].[OH-].[Na+]>O.C(O)C>[CH2:2]([C:1]1[CH:5]=[C:6]([OH:7])[N:24]=[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])[N:23]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCCOc1ccccc1C(=N)N
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(O)cc(CC)n1

Procedure:
A solution of ethyl propionylacetate (0.79 g), 2-propoxybenzamidine methanesulfonate (1.45 g) and sodium hydroxide (0.60 g) in water (5 ml) and ethanol (5 ml) was stirred at ambient temperature for 22 hours. Most of the solvent was removed under reduced pressure and water (20 ml) was added. The mixture was acidified to pH 2 with concentrated hydrochloric acid and then extracted with chloroform (3×30 ml). The combined extracts were washed with dilute acetic acid, dried (magnesium sulfate) and evaporated under reduced pressure to yield a residue which was recrystallized twice from ether to yield the title compound, 373 mg. m.p. 97°-98.5° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([NH:47]C=O)[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:33][CH2:32][N:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:45]=[CH:44][CH:43]=[CH:42][N:41]=7)=[CH:36][CH:35]=6)[CH2:30][CH2:29]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([NH2:47])[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:29][CH2:30][N:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:41]=[CH:42][CH:43]=[CH:44][N:45]=7)=[CH:36][CH:35]=6)[CH2:32][CH2:33]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=CNC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.3 %

Procedure:
Added 2M HCl (2 ml) to a solution of 3-Formylamino-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (6P) (10 mg, 0.015 mmol) in MeOH (2 ml) at room temperature, then stirred for 4 days at room temperature. The reaction mixture was diluted with Water (20 ml), basified with 1N NaOH (3 ml) and extracted with MeCl2 (3×50 ml). The organic layers were combined, dried over MgSO4, filtered and solvent evaporated yielding 7P as a white solid (7 mg, 73%) LCMS (MH 620.3) Retention time=2.78 minutes.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[CH:16]([CH:27]([CH2:29][CH3:30])[CH3:28])[NH:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]1([CH2:19][C:18]([NH:17][CH:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH:27]([CH2:29][CH3:30])[CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCC(C)C(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(C)C(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-phenylacetyl-D,L-isoleucyl-L-proline benzyl ester (1.2 g) was dissolved in methanol (15 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless sticky matter (939 mg, 97%), which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]([NH2:8])=O)=[CH:4][N:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]#[N:8])=[CH:4][N:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1C#N
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinamide (17) (2.5 g, 11.7 mmol) in DMF (10 mL), cyanuric chloride (11.7 mmol, 1 equiv.) was added at 0° C. and stirred for 2 h. The reaction mixture was quenched with ice-cool water and extracted twice using EtOAc. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography, silica gel (60-120 mesh) and EtOAc: pet Ether as eluent to furnish 6-chloro-4-(isopropylamino)nicotinonitrile. 1H NMR: 400 MHz, CDCl3: δ 1.32 (d, J=6.40 Hz, 6H), 3.69-3.79 (m, 1H), 4.91 (bs, 1H), 6.57 (s, 1H), 8.23 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 81 %

Procedure:
N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-ethylphenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as a tan solid in 81% yield.